Age-related neurodegenerative diseases including Alzheimer's disease (AD) and Huntington's disease (HD) are associated with mild impairment of oxidative metabolism, oxidative stress and accumulation of abnormal proteins. The underlying hypothesis of this program project is that "mitochondrial dysfunction in age-related neurodegenerative diseases promotes the development of disease and impairs the ability of the brain to adapt". The four project leaders have career long commitments to understanding the role of mitochondria and oxidative stress in normal and diseased brains with the goal of developing new therapies. Plausible mechanisms link the disease related mitochondrial abnormalities to the pathophysiology. Thus, an understanding of the causative (i.e., upstream events) as well as consequences (i.e. downstream events) of the mitochondrial change will help develop new therapeutic strategies. Our results in human brains at autopsy in numerous age-related neurodegenerative diseases reveal decreased activity of the mitochondrial enzyme a- ketoglutarate dehydrogenase complex (KGHDC) and an increased activity of transglutaminase (TGase). KGDHC is arguably the rate limiting step for NADH formations, produces ROS, is obligatory for heme production, and is very sensitive to oxidants. TGase is a cross linking enzymes that can modulate transcription, inactivate metabolic enzymes, and cause aggregation of critical proteins. Our recent data indicate that TGase can silence expression of genes involved in compensating for metabolic stress. The events upstream of these enzyme changes will be explored by testing for post-translational modification of enzymes and abnormal oxidant production in mitochondria from autopsy brains. Whether the consequences of the disease associated changes in TGase and KGDHC are protective or damaging is unclear. Therefore, the downstream consequences and therapeutic strategies will be tested at multiple levels of biological complexity: isolated proteins, gene transcription, cultured cells, fruit flies and transgenic mice. The proposed experiments will test whether increasing KGDHC via inhibition of TGase or via a host of other strategies would be effective therapeutic approaches in age-associated neurodegenerative diseases. Successful completion of the goals of these projects can be expected to provide new insights into neurodegenerative processes and contribute to novel approaches to ameliorating age-related neurodegenerations. PUBLIC HEALTH RELEVANCE: Age-related neurodegeneration diseases are devastating to the individual and to the economy. Abnormal sugar and oxygen use occurs in all of these and appears linked to the disease process. The proposed experiments are designed to determine what causes the problem, the consequences and how to correct the abnormalities. The experiments are designed to utilize the results to develop new therapies. REVIEW OF INDIVIDUAL COMPONENTS OF THE PROGRAM PROJECT CORE A: ADMINISTRATIVE CORE, DR. GARY E. GIBSON, Core Leader (CL) DESCRIPTION (provided by applicant): The administrative core will provide the support services which are necessary to the efficient functioning of the Program Project. Administrative as well as scientific coordination will be provided by the PI, Dr. Gary E. Gibson. Full staff meetings will be held regularly, to promote scientific interchange and coordination among the different Projects and Cores. These will include Drs. Beal and Starkov and their coworkers on the Manhattan Campus, as well as Drs. Ratan and Gibson in White Plains. A proportion of the meetings will be held in Westchester and at the Manhattan site (in conjunction with attendance at lectures of interest or other scientific presentations there), as well as by videoconferencing or web conferencing. The PI will also meet at least weekly, with the PPG administrative assistant to deal promptly with any administrative problems related to the Program Project. Dr. Vahran Haroutunian will continue to provide human brain samples from the ADRC at Mt. Sinai. Annual review will be provided by an External Review Committee (ERC). The current members of the ERC will continue to serve and the expertise of the members of the ERC include genetic manipulation of cells and mice, enzymology, protein chemistry, metabolism, and cell biology. The members of the ERC will also be available for more frequent ad hoc consultations on issues of their particular expertise. The core will also be responsible for coordinating development of new mice or viruses for manipulation KGDHC in cells or mice. PUBLIC HEALTH RELEVANCE: Age-related neurodegenerative diseases are major public health problems. This program project will test whether abnormal use of glucose and oxygen are critical to the disease process and are good therapeutic targets. Successful completion of the goals of these projects can be expected to contribute to novel approaches to ameliorating age-related neurodegenerative diseases.